Study reveals a new educational role for the entorhinal cortex

Study reveals a new educational role for the entorhinal cortex

A long-standing question in neuroscience is how mammalian brains (including ours) adapt to external environments, information, and experiences. In a paradigm-shifting study published in Nature, researchers at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children's Hospital and Baylor College of Medicine have discovered the mechanistic steps underlying a new type of synaptic plasticity called behavioral timescale synaptic plasticity (BTSP). The study led by Dr. Jeffrey Magee, a professor at Baylor who is also a Howard Hughes Medical Institute and Duncan NRI researcher, shows how the entorhinal cortex (EC) sends instructive signals to the hippocampus -; the brain region critical for spatial navigation, memory encoding and consolidation; and instructs it to specifically reorganize the location and activity of a particular subset of its neurons to achieve altered behavior in response to its changing environment and spatial cues.

Neurons communicate with each other by transmitting electrical signals or chemicals through connections called synapses. Synaptic plasticity refers to the adaptive ability of these neural connections to become stronger or weaker over time in direct response to changes in their external environment. This adaptive ability of our neurons to respond quickly and accurately to external signals is critical to our survival and growth and forms the neurochemical basis for learning and memory.

An animal's brain activity and behavior quickly adapt to spatial changes

To identify the mechanism underlying the mammalian brain's ability to learn adaptively, Dr. Christine Grienberger, a postdoctoral researcher in the Magee lab and lead author of the study, measured the activity of a specific group of place cells, which are specialized hippocampal neurons that create and update “maps” of external environments. She attached a powerful microscope to the brains of these mice and measured the activity of these cells while the mice ran on a linear treadmill.

In the initial phase, the mice were accustomed to this experimental setup and the position of the reward (sugar water) was changed with each round. "In this phase, the mice continuously ran at the same speed while continuously licking the track. This meant that the place cells in these mice formed a uniform tiling pattern," said Dr. Grienberger, who is currently an assistant professor at Brandeis University.

In the next phase, she attached the reward to a specific location on the track along with some visual cues to orient the mice and measured the activity of the same group of neurons.

I have seen that changing the reward location changed the behavior of these animals. The mice then stopped shortly before the reward point to taste the sugar water. And even more interestingly, this behavioral change was accompanied by increased density and activity of place cells around the reward site. This suggests that changes in spatial cues can lead to adaptive reorganization and activity of hippocampal neurons.”

Dr. Christine Grienberger, Assistant Professor, Brandeis University

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This experimental paradigm allowed researchers to examine how changes in spatial cues shape the mammalian brain to produce adaptive new behaviors.

For more than 70 years, Hebbian theory, colloquially summarized as "neurons that fire together, wire together," dominated neuroscientists' view of how synapses grow stronger or weaker over time. Although this well-studied theory forms the basis for several advances in the field of neuroscience, it has some limitations. In 2017, researchers in the Magee lab discovered a new and powerful type of synaptic plasticity – Behavioral Timescale Synaptic Plasticity (BTSP) – that overcomes these limitations and provides a model that best mimics the timescale of how we learn or remember related events in real life.

Using the new experimental paradigm, Dr. Grienberger found that in the second phase, previously silent place cell neurons abruptly acquired large place fields in a single round after the reward location had been established. This finding is consistent with a non-Hebbian form of synaptic plasticity and learning. Additional experiments confirmed that the observed adaptive changes in the hippocampal cells and behavior of these mice were indeed due to BTSP.

The entorhinal cortex instructs hippocampal place cells how to respond to spatial changes

Based on previous studies, the Magee team knew that BTSP involves an instructive/monitoring signal that is not necessarily within or adjacent to the activated target neurons (in this case, the cells of the hippocampal place). To identify the origin of this instructional signal, they examined the axonal projections of a nearby brain region called the entorhinal cortex (EC), which innervates the hippocampus and acts as a gateway between the hippocampus and neocortical regions that control higher executive/decision-making processes.

“We found that targeted inhibition of a subset of EC axons that innervate the CA1 hippocampal neurons from which we recorded prevented the development of CA1 reward overrepresentations in the brain,” said Dr. Magee.

Based on several lines of investigation, they concluded that the entorhinal cortex provides a relatively invariant target instruction signal that instructs the hippocampus to reorganize the position and activity of place cells, which in turn influences the animal's behavior.

"The discovery that one part of the brain (entorhinal complex) can instruct another brain region (hippocampus) to change the position and activity of its neurons (place cells) is an extraordinary discovery in neuroscience," added Dr. Magee added. “It completely changes our view of how learning-dependent changes occur in the brain and reveals new possibilities that will transform and guide our approach to neurological and neurodegenerative diseases in the future.”

This study was funded by the Howard Hughes Medical Institute, the Cullen Foundation, and the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital.

Source:

Texas Children's Hospital

Reference:

Grienberger, C & Magee, JC, (2022) Entorhinal cortex controls learning-related changes in CA1 representations. Nature. doi.org/10.1038/s41586-022-05378-6.

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